Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Cancer Res. 2022 Jun 6;82(11):2171-2184. doi: 10.1158/0008-5472.CAN-21-2428.
Cyclin-dependent kinase 4 (CDK4) and CDK6 are key cell-cycle regulators that are frequently dysregulated in human malignancies. CDK4/6 inhibitors are clinically approved for the treatment of hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, but improved specificity and reduced toxicity might expand their use to other indications. Through analysis of publicly available genome-wide loss-of-function data combined with single and dual-targeting CRISPR assays, we found differential cell proliferation vulnerability of cell lines to either CDK4 deletion alone, CDK6 deletion alone, combined CDK4/CDK6 deletion, or neither. CDK6 expression was the best single predictor of CDK4 (negatively correlated) and CDK6 (positively correlated) dependencies in the cancer cell lines, with adenocarcinoma cell lines being more sensitive to CDK4 deletion and hematologic and squamous cancer cell lines being more sensitive to CDK6 deletion. RB-E2F signaling was confirmed as a main downstream node of CDK4/6 in these experiments as shown by the survival effects of RB1 deletion. Finally, we show in a subset of cancer cell lines not dependent on CDK4/6 that CDK2-CCNE1 is an important alternative dependency for cell proliferation. Together, our comprehensive data exploration and functional experiments delineate the landscape of pan-cancer CDK4/6 gene dependencies and define unique cancer cell populations that might be sensitive to CDK4-selective or CDK6-selective inhibitors.
This study provides functional genomic insight toward understanding the scenarios in which cancer cells are differentially sensitive to CDK4 or CDK6 inhibition and their implications in current treatment strategies.
细胞周期蛋白依赖性激酶 4（CDK4）和 CDK6 是细胞周期的关键调节因子，在人类恶性肿瘤中经常失调。CDK4/6 抑制剂已被临床批准用于治疗激素受体阳性、HER2 阴性（HR+/HER2-）乳腺癌，但提高特异性和降低毒性可能会扩大其在其他适应症中的应用。通过分析公开的全基因组功能丧失数据，并结合单靶点和双靶点 CRISPR 测定，我们发现细胞系对单独 CDK4 缺失、单独 CDK6 缺失、联合 CDK4/CDK6 缺失或两者均缺失的细胞增殖脆弱性存在差异。CDK6 表达是癌症细胞系中 CDK4（负相关）和 CDK6（正相关）依赖性的最佳单一预测因子，腺癌细胞系对 CDK4 缺失更敏感，血液学和鳞状癌细胞系对 CDK6 缺失更敏感。RB-E2F 信号被确认为这些实验中 CDK4/6 的主要下游节点，正如 RB1 缺失的生存效应所表明的那样。最后，我们在一组不依赖 CDK4/6 的癌症细胞系中表明，CDK2-CCNE1 是细胞增殖的重要替代依赖性。总的来说，我们全面的数据探索和功能实验描绘了泛癌 CDK4/6 基因依赖性的全景，并定义了可能对 CDK4 选择性或 CDK6 选择性抑制剂敏感的独特癌症细胞群体。
这项研究提供了对理解癌细胞对 CDK4 或 CDK6 抑制的敏感性存在差异的情况的功能基因组见解，并对当前的治疗策略具有启示意义。
